Voltage-dependent calcium channels are ion channels that cause influx of calcium ions into cells under the potential difference between the interior and the exterior of a cell, and are known to have important biological functions, including neuronal excitation, synaptic transmission, muscle contraction, cardiac automaticity, secretion of neurotransmitters and hormones, cell proliferation and differentiation, and the like. Voltage-dependent calcium channels have been classified into any of the five categories T, L, P/Q, N, and R by their electrophysiological and pharmacological properties [Physiological Review, Vol. 83, p. 117 (2003)]. Of these five channels, only the T-type channels are activated by high membrane potentials, and are called low-voltage-activated channels. The other four channels are called high-voltage-activated (hereinafter, “HVA”) channels, because of their activation at low membrane potentials. As the name suggests, the T (transient)-type calcium channels are characterized by transient activation and quick inactivation. On the other hand, the HVA channels require a long time for inactivation.
It is known that the HVA channels basically function as a heterotetramer having α1, α2/8, β, and γ subunits. The α1 subunit is the subunit that forms a channel pore, whereas the other subunits function as regulatory or accessory subunits. On the other hand, it is believed that the T-type calcium channels function with the α1 subunit alone. To date, ten α1 subunits are known in voltage-dependent calcium channels, and three of these α1 subunits, α1G (Cav3.1), α1H (Cav3.2), and α1I (Cav3.3) are known to form the T-type calcium channels.
The expression of T-type calcium channels has been confirmed in various regions, including the peripheral and central nervous systems, heart, kidneys, smooth muscle, skeletal muscle, endocrine cells, bone, sperm, and the like. As physiological functions of the T-type calcium channels, neuronal firing, sleeping, pain transmission, heart's pacemaker function, renovascular tonus, hormone secretion, fertilization, and the like are reported [Physiological Review, Vol. 83, p. 117 (2003); Trends in Pharmacological Science, Vol. 30, p. 32 (2008); Proceedings of the National Academy of Science of the United States of America, Vol. 102, p 1743 (2005); Proceedings of the National Academy of Science of the United States of America, Vol. 101, p. 18195 (2004)].
As a disease associated with enhancement of the T-type calcium channels, epilepsy [Neuron, Vol. 31, p. 35 (2001); Annals of Neurology, Vol. 54, p. 239 (2003); Journal of Neurophysiology, Vol. 98, p. 2274 (2007)], pain [Channels, Vol. 1, p. 238 (2007); EMBO Journal, Vol. 24, p. 315 (2005); Journal of Neuroscience, Vol. 27, p. 3305 (2007); Molecular Cells, Vol. 25, p. 242 (2008); Acta Pharamacologica Sinica, Vol. 27, p. 1547 (2006); Genes, Brain and Behavior, Vol. 6, p. 425 (2007); Pain, Vol. 105, p. 159 (2003); Pain, Vol. 109, p. 150 (2004); Pain, Vol. 145, p. 184 (2009)], heart disease [Journal of Pharmacological Sciences, Vol. 99, p. 197 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 205 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 211 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 214 (2005)], kidney disease [American Journal of Kidney Disease, Vol. 38, p. 1241 (2001); Journal of Pharmacological Science, Vol. 99, p. 221 (2005); Circulation Research, Vol. 100, p. 342 (2007)], inflammation and edema [Pharmacological Research, Vol. 44, p. 527 (2001)], arteriosclerosis [Cardiology, Vol. 89, p. 10 (1998)], aldosteronism [The Journal of Pharmacology and Experimental Therapeutics, Vol. 287, p. 824 (1998)], cancer [Cell Calcium, Vol. 36, p. 489 (2004); Molecular Pharmacology, Vol. 62, p. 210 (2002)], hearing impairment [Hearing Research, Vol. 226, p. 52 (2007)], and the like have been reported. T-type calcium channel antagonists are thus considered effective for the treatment or prevention of these diseases. In fact, the cardioprotective effect [Circulation Journal, Vol. 67, 139-145 (2003); Circulation, Vol. 101, p. 758 (2000)] and the renoprotective effect [Hypertension Research, Vol. 30, p. 621 (2007)] of T-type calcium channel antagonists are reported in the clinic. Further, involvement of T-type calcium channels in sleeping [Proceedings of the National Academy of Science of the United States of America, Vol. 102, p. 1743 (2005); Proceedings of the National Academy of Science of the United States of America, Vol. 101, p. 18195 (2004)] is reported, and their antagonists are potentially effective for the treatment and/or prevention of sleep disorder [Current Opinion in Pharmacology, Vol. 8, p. 33 (2008)]. Further, in recent years, it was reported that T-type calcium channel antagonists may be effective for the treatment and/or prevention of pruritus (WO2010/110428).
From among the compounds that act on the T-type calcium channels, many compounds are known as, for example, T-type calcium channel inhibitors. Examples include efonidipine (see, Non-Patent Documents 1 and 2), mibefradil (see, Non-Patent Document 3), diphenylmethane derivatives (see, Patent Document 1), dihydroquinazoline derivatives (see, Patent Documents 2 and 3), piperidine derivatives (see, Patent Document 4), piperazine derivatives (see, Patent Document 5), azetidine and azetidone derivatives (see, Patent Document 6), thiazole derivatives (see, Patent Document 7), pyridine derivatives (see, Patent Document 8), and the like.
On the other hand, as the known imidazopyridine derivatives, imidazo[1,2-a]pyridine derivatives (A) having arylamino at the 7-position (see Patent Document 9), imidazo[1,2-a]pyridine derivatives (B) having aryl at the 2- or 3-position (see Patent Document 10), and the like are known. Also, imidazo[1,2-a]pyridine derivatives (C) having aminoalkyl at the 3-position (see Patent Document 11), imidazo[1,2-a]pyridine derivatives (D) having aralkyl at the 3-position (see Patent Document 12), imidazo[1,2-a]pyridine derivatives (E) having cycloalkyl at also the 3-position (see Patent Document 13), and the like are known. Yet imidazo[1,2-a]pyridine derivatives (F) having cycloalkylamino and the like at the 3-position (see Patent Document 14), imidazo[1,2-a]pyridine derivatives (G) having aroyl and the like at the 3-position (see Patent Document 15), imidazo[1,2-a]pyridine derivatives (H) having a hydroxamic acid side chain at the 7-position (see Patent Document 16), imidazo[1,2-a]pyridine derivatives (I) (see Patent Document 17) and (J) (see Patent Document 18) having a carbamoyl group at the 7-position, and the like are known. Compounds described in Patent Documents 20 to 35 are known yet as other examples of the imidazo[1,2-a]pyridine derivatives.
Furthermore, the imidazopyrimidine derivatives include imidazo[1,2-c]pyrimidine derivatives (K) having a carbamoyl group at the 7-position (see Patent Document 18), imidazo[1,2-a]pyrimidine derivatives (L) having aralkyl at the 3-position (see Patent Document 19), and the like are known.
